Process for the preparation of docetaxel trihydrate

ABSTRACT

A method to prepare Docetaxel trihydrate using the mixture of acetone and water, which provides the product with good stability, less experiment time, less exposal to light, and avoids purity decreasing. The process is simple and easy to operate.

FIELD OF THE INVENTION

This invention is under the field of medicine synthesization technique,involving the method to prepare the compound of Docetaxel trihydrate.

BACKGROUND OF THE INVENTION

The formal name of Docetaxel trihydrate is(2′R,3′S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with5β,20-epoxy-1β,2α,4α,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate-2-benzoate, trihydrate.

Docetaxel is a kind of new anti-cancer medicine that is being developedabroad in recent years. Being the representative of the 2nd generationof taxane medicine family, Docetaxel attracts more and more attentionfrom people for its enhanced water-solubility and wide spectrum ofexcellent anti-cancer characteristic. Docetaxel has activity againstseveral kinds of cancer, including breast cancer, non small cell lungcancer and other malignant tumours (prostate cancer, esophagus cancerand malignant tumour in head or neck, etc.), which is one of the mosteffective single medicine for treating the transferring breast cancer.The especially remarkable result of it is: in phase II clinical trial,for those patients who have received any chemotherapy (including thosepatient with primary resistence against anthracene, the totalchemotherapy efficiency of single Docetaxel was 47% (generally 100mgs/m², infusion, once per 3 weeks). A few research reports showed thatthe efficiency of this drug is between 32% and 58%, among which oneresearch reported CR (Complete Resultful) at 4%. For patients in thelater-stage of none small cell lung cancer, no matter he/she was in thebeginning of treatment, or has passed the progress of cis-platinumchemotherapy, the medicine proved its special anti-cancer activity.

Docetaxel can promote microtubule proteins to be assembled intomicrotubule and inhibit its disassembled. Docetaxel also has the goodbioavailability, higher intracellular concentration and longerintracellular retention-time.

Docetaxel is the first semi-synthesized taxus medicine. It has beenlaunched in the markets of Europe/America countries.

According to Chinese patent 95193984.X, Docetaxel trihydrate is morestable than its anhydrous compound. So we decided to add acrystallization process into the production procedure of the drugproduction. Ethanol and water are selected as solvents. But in thisexperiment process, the inventor discovered that use of the ethanolproduces not only more time expense for concentration and higher waterbath temperature, but also smaller crystal grain, thus longer time tofilter and collect products is needed.

SUMMARY OF THE INVENTION

The present invention provides a method to prepare Docetaxel trihydratehaving the following steps. Under temperature of 10-39° C., putanhydrous Docetaxel (purity of HPLC>99.5%) in 8˜12 parts acetone tofully dissolve. Then under the same temperature, and reduced pressureconcentrate it to form oil-like matter, add certain quantity of acetoneto fully dissolve, concentrate in reduced pressure again to formoil-like matter, then add certain quantity of acetone to fully dissolve,add dropwise certain quantity of purified water, the procedure will last10˜60 min. Control the dropping speed to avoid the growth ofagglomeration during the process. Then cool the product under 0° C. for2-5 hours, filter by suction, then wash the residue cake with themixture of acetone and water (1:1˜1:5), dry on P₂O₅ in vacuum till theweight is constant, the product obtained is Docetaxel trihydrate.

DETAILED DESCRIPTION OF THE INVENTION

This invention is to overcome the shortcoming of the above method and todesign an improved one. This invention offers a method to prepareDocetaxel trihydrate: Under temperature of 10-39° C., put anhydrousDocetaxel (purity of HPLC>99.5%) into 8˜12 parts (by weight) of acetoneto be fully dissolved. Then at the same temperature, under reducedpressure concentrate it to form oil-like matter, add certain quantity ofacetone to fully dissolve it, and concentrate it again to form oil-likematter, then add certain quantity of acetone to fully dissolve it, adddropwise certain quantity of purified water, the procedure will last10˜60 min. Control the dropping speed to avoid the growth ofagglomeration during the process. Then cool the product under 0° C. for2-5 hours, make suction filtration, then wash the residue cake with themixture of acetone and water (1:1˜1:5), dry it on P₂O₅ in vacuums tillthe weight is constant. The product is Docetaxel trihydrate.

The invention uses acetone and water to prepare Docetaxel trihydrate,which has the following advantages:

1. Less operation time. Because the crystal granule from acetone andwater is big, and this has shorten the filtration time. The crystalgranule from ethanol and water is smaller, so the filtration time is 3hours; while the time is 1 hour for acetone and water.

It is found during the experiment that Docetaxel's purity dropped whenit was exposed in light for 10 hours. It is sensitive to light in someway. Shortening of the filtration time decreased the exposure time, thusthe reduction of purity was avoided.

2. Lower operation temperature (below 40° C.). As Docetaxel's stabilityis bad in high temperature, this will help to avoid any purity drop ofDocetaxel in purification process.

A patent document mentions that the reaction temperature is 40˜60° C. ifethanol is used. But if acetone is used, the reaction may found ≦39° C.Lower temperature makes the experiment easier for operation.

The product from the invention process was proved to be compoundtrihydrate by methods of thermogravimetric analysis andthermo-differential analysis. Under the temperature of 55˜115° C., themass loss was 6.8%, which is in accordance with the 3 crystallized waterin the compound.

Product from this method was proved to have the same good stability asthat stated in the patent document. The experiment conditions fortesting the stability are: under temperature of 40° C., at relativehumidity of 75%, 12 months. Within this period, the trihydrate compoundremain no change.

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. All examples presented are representative and non-limiting.

The above-described embodiments of the invention may be modified orvaried, without departing from the invention, as appreciated by thoseskilled in the art in light of the above teachings. It is therefore tobe understood that, within the scope of the claims and theirequivalents, the invention may be practiced otherwise than asspecifically described.

EXAMPLE 1

Under 20° C., put 87 g anhydrous Docetaxel (purity of HPLC>99.5%) into1044 ml acetone to fully dissolve, then at 40° C. under reduced pressureconcentrate it to form oil-like matter. Add 348 ml acetone to dissolvethe oil-like matter, and again concentrated it to form oil-like matter.Add 1740 ml acetone to dissolve it well, then keep the temperature at15° C. and drop 2610 ml purified water slowly, which lasts 15 min. Thedropping speed should be controlled to avoid agglomeration. After that,cool it under 0° C. for 2 hours and then make suction filtration. Thenwash the residue 3 times with 200 ml mixture of acetone and water(1:1.5). Dry it on P₂O₅ in vacuums for 5 hours till it obtains aconstant weight. The trihydrate compound is 85 g with 6.43% of watercontent.

EXAMPLE 2

Under 40° C., put 200 g anhydrous Docetaxel (purity of HPLC>99.5%) into2850 ml acetone to fully dissolve, then at 40° C., under reducedpressure concentrate it to form oil-like matter. Add 950 ml acetone todissolve the oil-like matter, and again concentrated it to form oil-likematter, add 4750 ml acetone to dissolve it well, then keep thetemperature at 15° C. and drop 9975 ml purified water slowly, whichlasts 50 min. The dropping speed should be controlled to avoidagglomeration. After that, cool it under 0° C. for 4 hours and then makesuction filtration. Then wash the residue 3 times with the 580 mlmixture of acetone and water (1:3.5). Dry it on P₂O₅ in vacuums for 6.5hours till it obtains a constant weight. The compound is 196.5 g with6.2% of water content.

1. A method for preparing Docetaxel trihydrate, comprising: dissolvinganhydrous Docetaxel in acetone at a ratio of about 1:(8-12) by weight toform a mixture, concentrating the mixture to form an oil-like matter andre-dissolving the oil-like matter in acetone to obtain a solution,adding dropwise purified water to the solution while controlling dropspeed to avoid growth of agglomeration, and cooling the solution toobtain crystalline Docetaxel trihydrate.
 2. The method according toclaim 1, wherein the anhydrous Docetaxel is dissolved in acetone atabout 10-39°C.
 3. The method according to claim 1, wherein the anhydrousDocetaxel has a purifty of HPLC>99.5%.
 4. The method according to claim1, wherein the concentration of the solution of Docetaxel to form theoil-like matter is repeated, and the oil-like matter is dissolved inacetone to form a solution.
 5. The method according to claim 1, whereina duration for adding purified water dropwise lasts about 10-60 minutes.6. The method according to claim 1, wherein the solution is cooled at0°C. for about 2-5 hours.
 7. The method according to claim 6, furthercomprising suction-filtering the solution to obtain a residue cake,washing the residue cake in a mixture of acetone and water, and dryingthe washed residue cake to obtain the Docetaxel trihydrate.
 8. Themethod according to claim 7, wherein the residue cake is washed in themixture of acetone and water at a ratio of about 1: (1-5).
 9. The methodaccording to claim 7, wherein the washed residue cake is dried on P₂O₅in vaccum until weight of the residue cake is constant.